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Multiple Mechanisms of Resistance to Camptothecins

Multiple Mechanisms of Resistance to Camptothecins

May 01, 2001

NEW BRUNSWICK, New JerseyAlthough camptothecins can cure
colon cancer in animals, they are active but not curative in human tumors. The
question of why drugs that are effective in animal models are sometimes less
effective in clinical studies, as well as issues related to resistance to
cytotoxic drugs were discussed by Eric H. Rubin, MD. Dr. Rubin is associate
professor at the Cancer Institute of New Jersey, Robert Wood Johnson Medical
School in New Brunswick.

"The topoisomerases have been exploited by nature as good
targets for cytotoxicity," Dr. Rubin said. "There are many naturally
occurring antibacterial and antineoplastic compounds that target
topoisomerases."

The catalytic mechanism of topoisomerase I involves binding,
cleavage, controlled rotation, religation, and release (Figure 1).
"Possible mechanisms of resistance to irinotecan [Camptosar] seen in cell
culture models include alterations in irinotecan metabolism, cellular
accumulation of irinotecan or SN-38, SN-38 interaction with the topoisomerase
I-DNA complex, and processing of topoisomerase I-mediated DNA damage," Dr.
Rubin explained. "Cell culture models provide evidence for multiple
mechanisms of irinotecan resistance, but clinical relevance has not been
established for any of the resistance mechanisms identified in cell culture
models."

Several Mechanisms Reported

Decreased carboxylesterase activity and increased
glucuronidation have been reported in several irinotecan-resistant cell lines.
Variable carbox-ylesterase activity has been observed in both normal and tumor
tissues. Dr. Rubin said that the ratio of tumor to normal cell carboxylesterase
activity is probably critical in determining the therapeutic index of
irinotecan.

A second resistance mechanism involves the failure of
irinotecan/SN-38 to accumulate in the cell nucleus. "Drug efflux is
clearly implicated in certain resistant cell lines," Dr. Rubin said. This
is thought to involve efflux proteins including P-glycoprotein, MRP-1, cMOAT,
PDR5, SNQ2, and BCRP/MXR/ABCP.

"There appears to be analogue specificity to this
process," Dr. Rubin said. "BCRP/MXR/ABCP affects topotecan [Hycamtin]
and SN-38, but not the parental drug camptothecin."

A third mechanism of resistance occurs when SN-38 does not
stabilize the cleavable complex. Dr. Rubin said that topoisomerase I
down-regulation or mutation is commonly observed in resistant cell lines and
that variable levels of topoisomerase I have been reported in tumor specimens.
Resistance-conferring mutations have not yet been reported in clinical
specimens, however, and one negative study published found no mutations in 56
patients with lung cancer.

Resistance can also occur if the drug does not stabilize the
cleavable complex due to mislocalization of topoisomerase I. Dr. Rubin said
that this can result from ubiquitination of topoisomerase I.

"Camptothecin treatment leads to rapid topoisomerase I
ubiquitination and down-regulation in cells, and camptothecin-induced
topoisomerase I degradation correlates with sensitivity in cell lines,"
Dr. Rubin said.

Resistance may also occur if camptothecin-stabilized cleavable
complexes do not result in cell death.

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